This application represents the first competing renewal of our program project, which uses an interdisciplinary team approach to address the unifying hypothesis that most, if not all, aging-related neurodegenerative disorders are caused by the intracellular or extracellular accumulation of specific proteins that have assumed pathogenic conformational states (proteinopathies). The resulting neurodegenerative disorders, which include Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD) and other Lewy body diseases (LED), remain largely untreatable and represent a complex biomedical, behavioral and social problem. Medical breakthroughs are urgently needed in this area, and the surest way to such breakthroughs is to determine how exactly these diseases result in the dysfunction and degeneration of nerve cells. Our program addresses this important need by bringing together investigators with diverse areas of expertise, widely overlapping interests in proteinopathies, and an established track record of fruitful collaborative interactions. Our approach takes advantage of a great number of valuable resources and technologies, including robotic microscopy, molecular imaging, genetically engineered mouse models, RNAi mediated gene silencing, and cell type-specific expression of mechanistically informative viral constructs. Using these and other strategies, we will study the processes by which diverse proteins impair neuronal function and survival and compare our results to determine whether there are common mechanisms of neurodegeneration. We will also study the susceptibility of different neuronal populations to common versus disease-specific pathogenic processes to elucidate why these diseases so selectively attack specific neuronal populations. Project 1, "Mechanisms of Cell-Specific Huntingtin-lnduced Neurodegeneration" aims to elucidate cell autonomous and cell non-autonomous mechanisms that contribute to the susceptibility of striatal neurons to mutant huntingtin. Project 2, "Microglial Kynurenine Pathway and Selective Neuronal Vulnerability," will test if genetic or pharmacological inhibition of the microglial kynurenine pathway is protective in mouse models of AD and HD. Project 3, "Apolipoprotein E in Alzheimer's Disease: Cellular Mechanisms," will study the regulation of apolipoprotein E expression in neurons and explore Apin dependent roles of different apolipoprotein E isoforms in the pathogenesis of AD. Project 4, "Causes and Consequences of a-Synuclein Aggregation," will assess in combined models of AD and PD if interactions between a-synuclein and A[unreadable] lead to neurodegeneration of specific neuronal populations through activation of glutamate receptors and proteases that cleave a-synuclein. Project 5, "Mechanisms of Aft-Induced Neuronal Deficits," will test whether the modulation of specific neuronal or glial molecules can block aberrant neuronal overexcitation and ameliorate behavioral abnormalities in mouse models of AD and other proteinopathies. The Cores (A: Administrative, B: Tissue Culture, C: Animal, D: Microscopy/Neuropathology) will provide the common services necessary to accomplish the goals of the program project. Our studies will shed light on diverse neurodegenerative diseases and could provide the knowledge needed to better treat and prevent them. PRINCIPAL INVESTIGATOR: Dr. Lennart Mucke is a Distinguished Professor at UCSF and Director of the Gladstone Institute of Neurological Diseases (GIND). He is a demonstrated and accomplished leader in the neurodegenerative disease field with broad clinical and basic expertise applicable to all aspects of the PPG. He has effectively coordinated a highly successful first term of the PPG involving a team of investigators at multiple sites, with whom he has interacted productively. Recently, Dr. Mucke has overseen a successful relocation of the Gladstone laboratories of the PPG to a new location on the Mission Bay campus. He is eminently qualified to continue to lead this PPG. REVIEW OF INDIVIDUAL COMPONENTS CORE A - Administrative Core, Dr. Lennart Mucke DESCRIPTION (provided by applicant): Core A will be responsible for the general organization of the program and for promoting productive interactions among all projects and cores and between this program and the scientific community. The core will also promote, monitor, and report on the progress of the program. To achieve these goals, we propose the following specific aims. Aim 1: Define the overall organization of the program and adjust its structure according to research developments and opportunities. The core leader has developed an interactive program in disease-related neuroscience at the applicant institution, and the current proposal emerged directly from these research activities. The proposal also relates closely to the core leader's long-standing and fruitful collaboration with Dr. Masliah at UCSD, whose interests overlap widely with those of the other members of this program. Aim 2: Promote exchange among the projects and cores and monitor their progress toward the goals of the program. Research in this program will be carried out in five projects and four cores. Core A will organize regular meetings of all program personnel to review and discuss progress and adjust experimental strategies as needed. We will continue to encourage and facilitate the development of web pages and databases to promote the exchange of information among program members. Aim 3: Ensure the efficient generation and safe storage of data, the timely preparation of progress reports, and the dissemination of research findings and materials. This will include instruction in safety procedures, backup of electronic files, and assistance with manuscript preparation, travel arrangements, and shipments of materials. Aim 4: Arrange for external reviews of the research activities in the projects and cores and foster the acquisition of new approaches that could promote the progress of the program as a whole. The entire program will be reviewed annually by members of an external advisory board. Additional experts will be invited to provide ad hoc input on specific components. Aim 5: Play an active role in the further development of UCSF's Mission Bay campus and help the project/core leaders take advantage of the many conceptual and technological advances that will emerge at this site. During the preceding funding period, we relocated all three Gladstone Institutes, and with them most of this program, to the Mission Bay campus. By consolidating our laboratories, cores, and animal care facilities into the same research building located within walking distance from many UCSF colleagues with overlapping interests, this move further enhanced the strength and potential of our program. Our new environment will greatly contribute to the success of the research proposed in this renewal application.